HIV infection continues to rise in drug users, putting them at greater risk of developing dementia. The pathobiology of HIV dementia is only partly understood, however, it is clear that disruption of the blood brain barrier facilitates the entry of peripheral blood monocytes into the brain. Activated and HIV-1 infected monocytes within the central nervous system (CNS) can in turn damage neighboring cells through the release of infectious virus and/or potent neurotoxins. It has recently been shown that drugs of abuse such as cocaine can disrupt the blood brain barrier (BBB), though the associated mechanisms are not well understood. Critical components of this barrier include extracellular matrix proteins such as collagen IV and laminin. Extracellular matrix proteins are regulated by an endogenous family of proteins called matrix metalloproteases (MMPs). These proteases are released not only by activated T cells and monocytes as they migrate through the BBB, but also by resident cells of the brain parenchyma. It has been shown that injection of MMPs into the parenchyma of the brain causes a disruption of the BBB which is followed by leukocytic infiltration of the central nervous system (CNS). Moreover, MMPs produced within the brain parenchyma may have more direct effects on CNS structure and function in that extracellular matrix proteins are known to affect synaptic structure as well as neuronal survival. In the present study, we will therefore address the possibility that both HIV-1 proteins and drugs of abuse will increase MMP production by brain-derived cells. We will also examine the mechanisms by which these substances may affect MMP production, and identify clinically tolerable compounds which may inhibit such production.